As inorganic porous articles to be used for clinical purposes, for example, porous ceramics obtained by calcining or sintering bioceramics are known. However, since such porous ceramics show a disadvantage of being hard but friable when used in applications such as a scaffolding for living bone tissue reconstruction, a prosthetic material and the like, there always is a danger of causing destruction by a slight impact after the operation. Also, it is difficult to process and change the shape of porous ceramics to match to the shape of the damaged part of a living bone tissue in the field of operation, too. In addition, since 10 years or more of a prolonged period of time is required in some cases until it is completely replaced by a living bone, a danger of causing harmful effects by its destruction remains during this period.
On the other hand, as organic porous articles to be used for clinical purposes, for example, a sponge and the like disclosed in JP-B-63-64988 are known. This sponge is generally used for the blood stanching at the time of surgical operation or as a prosthetic material at the time of the suture of a soft tissue (e.g., an organ) in the living body, which is a sponge having continuous pores comprising a biodegradable and bioabsorbable polylactic acid. Such a sponge is produced by a method in which polylactic acid is dissolved in benzene or dioxane, and the solvent is sublimed by freeze-drying the polymer solution.
However, regarding a porous article produced by a freeze drying method such as the case of the above sponge, it is difficult to remove the solvent completely because it requires a prolonged period of time for the sublimation, and since it has a thin thickness of 1 mm or less (generally about several hundred μm), it is difficult in reality to produce a porous article having a thickness of several mm or more. As other methods for producing porous articles having continuous pores, various methods have been examined in addition to the aforementioned freeze drying method, but it is not easy to obtain a thick porous article of several mm or more. It is impossible to apply such a thin porous article in compliance with the shape of, for example, a complex and relatively large three dimensional space of a damaged part of a living body tissue, thereby allowing it to exert its function as a temporal prosthetic material and simultaneously effecting three dimensional tissue reconstruction of the damaged part. Accordingly, there is a demand for those which has thickness, and can be made into a three dimensional cube before or during an operation, and are degraded and absorbed and replaced by a living bone at a relatively early stage.
Also, an elution method is known as another reliable method for making a porous article having continuous pores, in which a large amount of a water-soluble powder having a certain size such as NaCl is mixed with a polymer, and the mixture is formed into a sheet or the like thin molding and then soaked in water (solvent) to effect elusion of said powder, thereby forming continuous pores having the same diameter of said powder, but since it is difficult to elute said powder completely, the products are limited to thin article of continuous pores. Also, continuous pores can hardly be obtained when ratio of the water-soluble powder becomes high. What is more, when this porous article is embedded into the living body, it causes a problem of being encumbered with the toxicity of said powder still remaining.
Like the case of the aforementioned sponge, a porous article which does not contain bioactive bioceramics and the like inorganic powders is lacking direct bindability, conductivity, replaceability and the like with bone, cartilage and the like bone tissues in the living body, so that not osteoblast but fibroblast and the like soft tissues are penetrated and present therein, thus requiring a considerably prolonged period of time until the bone tissue in the living body is completely replaced and regenerated, or it ends up un-replaced.
Accordingly, the present applicant has already applied for a patent on a thick porous article having continuous pores comprising a biodegradable and bioabsorbable polymer, wherein a bioactive bioceramics powder is contained inside thereof, which becomes a scaffold of a three dimensional cube when osteoblast is inoculated and can be transplanted into a damaged part of a large bone for mediation (Japanese Patent Application No. 8-229280).
This porous article is produced by a porous article production method called solution precipitation method. That is, by a method in which a suspension is prepared by dissolving a biodegradable and bioabsorbable polymer in a mixed solvent of its solvent with a non-solvent having a boiling point higher than that of the solvent and simultaneously dispersing a bioceramics powder therein, and the bioceramics powder-including biodegradable and bioabsorbable polymer is precipitated by evaporating the mixed solvent from this suspension at a temperature lower than the boiling point of the solvent.
The principle for forming a porous article by this solution precipitation method is as follows. That is, when the mixed solvent is evaporated from the aforementioned suspension at a temperature lower than the boiling point of the solvent, ratio of the non-solvent having higher boiling point is gradually increased by preferential evaporation of the solvent having lower boiling point, and the solvent becomes unable to dissolve the polymer when the solvent and non-solvent reach a certain ratio. Because of this, the polymer starts its deposition and precipitation and includes the bioceramics powder which is starting its precipitation from the beginning, the thus deposited and precipitated polymer is shrunk and solidified by the high ratio non-solvent and fixed while including the bioceramics powder, and a cell structure in which the mixed solvent is included is formed on the connected thin cell walls of the polymer. Thereafter, the remaining solvent evaporates and disappears while making pores by destroying parts of the cell walls, and the non-solvent having higher boiling point also evaporates gradually through said pores and completely evaporates and disappears in the end. As a result, a bioceramics powder-containing porous article is formed, in which remains of the mixed solvent reservoirs included in the polymer cell walls are connected as continuous pores.
The aforementioned solution precipitation method is an epoch-making method which can form a thick porous article having from a low expansion ratio to a high expansion ratio, and it is possible to obtain a block-shaped three dimensional porous article having a thickness of from several mm to several ten mm. Accordingly, this is markedly useful for, e.g., a scaffold of the regeneration of a solid shape (three dimensional solid shape) bone having large relief.
However, this method has a disadvantage in that a bioceramics powder belonging to a relatively large particle diameter among the particle diameter distribution in a suspension containing the bioceramics powder in a large amount starts its precipitation from the beginning of the solvent evaporation, and a fairly large amount of the bioceramics powder is already starting its precipitation with a density gradient toward the bottom when the polymer starts its deposition and precipitation, so that the bioceramics powder content of the thus obtained porous article is not uniform as a whole and it is not avoidable therefore that the content increases from the upper side toward the bottom side of the porous article. Such a heterogeneous porous article having a density gradient of the content cannot be used efficiently and indiscriminately for its applications such as a scaffold for bone tissue reconstruction, a prosthetic material, a bone filler and the like. It is possible to improve such a problem to a certain degree by controlling sedimentation velocity and the like of the bioceramics powder by a certain method, but it cannot be solved completely. Particularly, it is difficult, not only by the invention but in general, to prepare a porous article for three dimensional bone reconstruction use containing 30% by weight or more of a bioceramics powder and having a homogeneous and uniform concentration.
Regarding the porous article having a small content of bioceramics powder produced by the aforementioned method, the majority of the bioceramics powder is included in the polymer cell wall and can hardly be exposed to the inner face of the continuous pores and the surface of the porous article, so that it has a problem in that when embedded in the living body, conduction action of a living bone tissue by the bioceramics powder can hardly be exerted from just after the embedding, and the bioactivity therefore is exhibited having a time lag together with the bioceramics powder exposed at the same time with the degradation of the polymer which forms a skin layer.
Also, even when extremely fine particles are selected as the bioceramics powder, its percentage content in the porous article produced by the aforementioned method is up to about 30% by weight at the most, and when it is contained in an amount larger than this, the bioceramics powder becomes more apt to precipitate so that the bottom side of the thus obtained porous article contains a large amount of the bioceramics powder and therefore becomes extremely brittle.
In addition, the porous article produced by the aforementioned method generally has continuous pores in a large occupying ratio of 80% or more, but in generally saying, only continuous pores having a relatively small pore diameter of from several μm to several ten μm are obtained so that it cannot always say that the pore diameter and pore shape ideal for the penetration and proliferation of osteoblast into and in the porous article are formed.
Methods for highly filling inorganic powder substances have been examined by other methods than the aforementioned solution precipitation method of the present applicant, and one of the influential methods among them is a method for preparing an article of continuous pores by a baking method in which granules are prepared by filling a polymer with about 50% by weight of a bioceramics powder, and these particles are fused on the surface by heating. This method is not a brand-new method but well known as a method for preparing a porous article of a granular resin such as an epoxy resin, a vinyl chloride resin or the like. Since this method requires surface fusion, the filling amount has a limitation and 50% by weight or more of filing is hard to achieve due to generation of brittleness, and control of the pore diameter is not easy too, so that a product having good quality can hardly be obtained.
The invention aims at providing various implant materials comprising an organic-inorganic complex porous article highly filled with inorganic particles, which can resolve all of these problems, and production methods thereof. In addition, it also contemplates providing implant materials comprising combinations of this organic-inorganic complex porous article with other living body materials, which are used as bone fixing materials, used as vertebral body fixing materials [intervertebral installation material and vertebral body prosthetic material] and the like, used as substitutes for bone allograft, bone autograft, cortical bone, spongy bone or combinations thereof, used as prosthetic and filling materials and the like for defect parts and deformed parts of bones, used as scaffolds for bone and cartilage formation, and used as artificial cartilage.
Currently, a bone fixing material such as a fixing pin comprising a biodegradable and bioabsorbable polymer is used, which is embedded by bridging the marrow of both sides of an incised part of the sternum, for example, in the surgical operation of sternum splitting incision closing. Since this is gradually degraded and absorbed in the sternum, it has an advantage of not requiring its extraction from the living body by carrying out re-operation like the case of pins made of non-absorbable ceramics or metals, but since it has no bone conduction and does not directly bind to a bone tissue, it merely has an effect to close the incised face through provisional fixing of the closed sternum by exerting an action as a simple “wedge”. Because of this, when the spongy bone becomes brittle by changing into a wafer retaining only a thin cortical bone as can be seen in the majority of the sternum of the aged, it causes problems in that even when this fixing pin for the sternum is embedded, it is difficult to increase fixing stability by exerting its action as the “wedge” and it is not replaced by a bone tissue. On the other hand, porous articles of hydroxyapatite (HA) and the like ceramics, which are used for the connection and fixation of cut regions and fractured regions of bones other than the sternum, have problems in that they are apt to break and require a considerably prolonged period of time to be absorbed in the living body. Though there is an opinion that there is no problem even when a prolonged period of time is required, because its strength is restored once embedded in the living bone, but there still is a danger of causing breakage until it is completely embedded. The implant materials of the invention to be used as bone fixing materials mainly aim at resolving these problems.
In this connection, a conventional vertebral body fixing material such as a cage made of titanium or carbon to be used as an intervertebral spacer in the anterior interbody fusion for lumbar spine degeneration diseases satisfies chemical biocompatibility of the surface for the present, but since dynamical biocompatibility is different from the living body, there are problems such as a danger of exhibiting harmful effect on the peripheral tissues by periodical breakage and corrosion due to its protracted presence as a foreign matter in the living body. For example, there is a problem in that the cage subsides into the vertebral body via a osseous endplate exposed by reaming, generated due to disharmony of dynamical characteristics between the cage and the living body. Particularly, being hard but brittle, a cage made of carbon is broken along its carbon fibers and generates fine pieces in some cases, so that a possibility of exhibiting harmful effect thereby always remains. Also, a bone for autograft to be filled in these cages is generally supplied by extracting an ilium, but there are a problem regarding its amount and preparation and a problem in terms of complicated treatments after the extraction (after treatment of the extracted region, and pulverization, filling in the cage, treatment under sterile condition and the like of the ilium). The implant materials of the invention to be used as vertebral body fixing materials mainly aim at resolving these problems.
On the other hand, an operation for making up defect parts of bones is usually carried out in recent years making use of a bone allograft prepared by cutting and processing a cadaveric bone or a bone autograft extracted from a region of a large bone such as the pelvis, a rib or the like. When the bone allograft is in a block shape integrated by providing a cortical bone on the surface of a spongy bone, a cortical bone region of a defect position of a bone can be made up by the cortical bone of said allograft, a spongy bone region of a defect position of a bone can be made up by the spongy bone of said allograft. However, since the bone allograft is prepared by cutting and processing a cadaveric bone, it poses a problem in that it is not easy to provide necessary and sufficient amount of graft bone by obtaining the material cadaveric bones in a large amount, and it also poses a problem in that workable shapes are greatly limited. Also, even in the case of a bone allograft, the transplanted said graft bone is a bone tissue different from its own bone tissue, there is a possibility that it disappears by its spontaneous absorption and its strength becomes insufficient or is reduced, depending on the embedding conditions. In addition to this, it is necessary to carry out a sterilization treatment because it is a cadaveric bone of other person, but since denaturation of the cadaveric bone occurs depending on its conditions, it is necessary to control sufficient sterilization conditions. However, since it is insufficient sometimes, there is a case in which generation of a serious accident extending to death is announced after its embedding. Though such an accident can be avoided by a bone autograft extracted during an operation, it cannot be denied that its amount is insufficient. On the other hand, embedding of implant materials made of hydroxyapatite (HA), tricalcium phosphate (TCP) and the like bioactive ceramics are also carried out at a defect part, but in that case, there is a problem in that a cortical bone region and a spongy bone region of a defect position of a bone are evenly made up by the hard ceramics, and since such ceramics remain semipermanently, it still poses a problem of being not able to reconstruct the defect position of bone by a self bone tissue. Thus, a method for obtaining a substitution for the spongy bone by preparing porous articles of said ceramics is becoming considerably realistic. However, since it is the best ideally that these synthetic artificial bones are replaced by living bones, when they are replaced after a prolonged period of 10 to 20 years, an accident as a physical foreign matter during this period must be feared in sometimes. The implant materials of the invention to be used as substitutes for bone allograft and bone autograft mainly aim at resolving these problems.
In addition, a punching (mesh shape) plate made of titanium or the like metal in which a large number of pores are formed by punching, a punched flat plate or rugged plate comprising a compact article or porous article of baked bioceramics, and the like, are used as conventional prosthetic, filling and coating materials of defect parts and deformed parts of bones. However, since the punching plate made of a metal lacks in physical biocompatibility and remains permanently as a foreign matter in the made-up region, there is a danger of exhibiting harmful effect on the peripheral tissues caused by corrosion, metal ion elution and the like during its long-term embedding, so that there is a problem in that the defect parts cannot be completely replaced at all by a bone tissue. In addition, since the porous article of baked bioceramics is hard but brittle and easily broken, there is a danger of being broken by receiving impact during its use and there is a problem in that it cannot be post-formed during an operation to match the three dimensional shape of the defect part of bone. The implant materials of the invention to be used as prosthetic, filling, coating and the like materials mainly aim at resolving these problems.
In addition, a conventional artificial cartilage, for example, a total replacement type independent artificial intervertebral disk is an artificial intervertebral disk having a so-called sandwich structure in which two metal endplates made of titanium or cobalt-chromium are superposed on both sides (upside and down side) of a core comprising bio-inactive polyethylene or a rubber having biocompatibility, wherein the core portion performs a movement similar to that of the living intervertebral disk depending on the superposing condition of the two sheets of polyethylene and, in the case of a rubber, it is imitated by its elasticity. In order to give effect of its independence by preventing slipping when inserted between vertebral bodies, it is made into a structure in which several horns are projected on the surface of the metal plate so that they are fixed by sticking into concave of the vertebral body. However, since this artificial intervertebral disk has a sandwich structure of materials having different qualities from those of the living body, it has great disadvantages in that abrasion is formed between their interface after repetition of movement, it cannot be said by no means that the movement is the same as that of the living intervertebral disk, and the horns projected from the metal plate not only injure the upper and lower vertebral bodies but also cause still more damages by gradually subsiding and penetrating into the vertebral bodies during its use for a prolonged period of time, so that it cannot be independently fixed by directly binding to the upper and lower vertebral bodies. The implant material of the invention to be used as an artificial cartilage mainly aims at resolving these problems, and by intervening the porous article of the invention between vertebral bodies including the endplate, it also aim at effecting close contact by filling a physical gap with said artificial intervertebral disk, and also at effecting direct bonding with the vertebral body by the bone conduction.